CN105838600A - Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode - Google Patents
Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode Download PDFInfo
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Abstract
The invention discloses a method for online synthesizing 5'-O-palmitoyl uridine in a lipozyme catalysis mode .The method includes the steps that dimethyl sulfoxide and tert-amyl alcohol with the volume ratio of 1:(8-16) serve as a reaction solvent, uridine and palmitic acid vinyl ester with the molar ratio of 1:(5-13) serve as raw materials, 0.5 g to 1.0 g of lipozyme TLIM serves as a catalyst, the raw materials and the reaction solvent are placed into an injector, a reaction channel of a microfluidics channel reactor is evenly filled with the lipozyme TLIM, and the raw materials and the reaction solvents are continuously led into a reaction channel device under pushing of an injection pump for an acylation reaction, wherein the inner diameter of the reaction channel of the microfluidics channel reactor is 0.8 mm to 2.4 mm, the length of the reaction channel is 0.5 m to 1.0 m, the temperature of the acylation reaction is controlled to be 15 DEG C to 50 DEG C, the concentration of the uridine in the reaction system is 0.03 mmol/mL to 0.07 mmol/mL, and the time of the acylation reaction is 20 min to 35 min; reacted liquid is online collected through a product collector and subjected to conventional aftertreatment, and the 5'-O-palmitoyl uridine is obtained .The method has the advantages of being short in reaction time and high in selectivity and yield.
Description
(1) technical field
A kind of method that the present invention relates to lipase-catalyzed online controlled selectivity synthesis 5'-O-palmityl uridnine
(2) background technology
Nucleoside medicine occupies an important position in the treatment of viral disease.In the antiviral drugs used clinically at present,
Nucleoside medicine proportion reaches more than 60%.Most nucleoside compounds is polyol, has that polarity is higher, intestinal
Road permeability is relatively low, the defect such as fat-soluble difference, toxic and side effects be big and oral administration biaavailability is relatively low.Nucleoside compound passes through
After esterification is modified, can strengthen that it is fat-soluble, improve pharmacologically active, improve its oral administration biaavailability.At common chemical method ester
During change, multiple hydroxyls are likely to participate in esterification, and product is the mixture of monoesters and polyester, thus needs through " radical protection
Esterification deprotection group " three steps could obtain single position be esterified product.And enzyme has good specificity and choosing to substrate
Selecting property, can be esterified certain hydroxyl of nucleoside with selectivity, and reaction selectivity is higher, decreases the tired of product later separation
Difficulty, therefore biocatalysis technology plays the most important role in the esterification of nucleoside compound.
Micro-fluidic (Microfluidics) is that manipulation nanoliter, to the technology of picoliters volume fluid and science, is near in micron scale construction
The new cross discipline emerged rapidly over 10 years.Currently, the development of micro-fluidic has surmounted original predominantly analytical chemistry the most significantly
The purpose of service, and becoming whole chemistry subject, life sciences, instrumental science or even information science new round innovation research
Important technological platform.
After Harrison seminar in 1997 has delivered the document that a first piece synthesizes compound in micro-fluidic chip microreactor, micro-
Fluidic chip reactor has been successfully used to multiple organic synthesis, and illustrates the prospect of being widely applied.Along with micro-fluidic core
The development of microring array, micro-reacting tcchnology in sheet, carries out synthetic reaction in the chips and has become as the research heat in micro-fluidic chip field
One of point.
Compared with conventional chemical reactor, micro passage reaction not only has makes the diffusion length between reactant be greatly shortened, and
Mass transfer velocity is fast；The easy control of reaction conditions such as reactant ratio, temperature, response time and flow velocity, side reaction is less；Need
Reactant consumption is little, not only can reduce costliness, poisonous, the consumption of adverse reaction thing, the environmental pollution produced in course of reaction
Thing is also few, is a kind of environmental friendliness, the technology of study on the synthesis novel substance.
At present, there is more Chinese scholars that the Enzyme catalyzed synthesis of nucleoside acylation reaction in organic media is studied, but
The method many selections acylase is catalyzed, and generally requires the longer response time (12-24h), and the conversion ratio of reaction and selection
Property is the highest, therefore we have studied the method for lipase-catalyzed online synthesis 5'-O-palmityl uridnine in micro passage reaction, it is intended to
Find the online controlled method for selective synthesis of the 5'-O-palmityl uridnine of a kind of high-efficiency environment friendly.
(3) summary of the invention
The technical problem to be solved in the present invention is to provide lipase-catalyzed online synthesis 5'-O-palm fibre in a kind of microfluidic channel reactor
The new technology of palmitic acid ureide glycosides, has the advantage that the response time is short, productivity is high, selectivity is good.
For solving above-mentioned technical problem, the present invention adopts the following technical scheme that
A kind of method of lipase-catalyzed online synthesis 5'-O-palmityl uridnine, described method uses microfluidic channel reactor, institute
The microfluidic channel reactor stated includes that syringe pump, syringe, reaction channel and product collector, described syringe are installed on note
Penetrating in pump, be connected with reaction channel entrance by an interface, described product collector is exported with reaction channel by an interface
Connecting, described reaction channel internal diameter is 0.8～2.4mm, reaction channel a length of 0.5～1.0m；Described method includes: with volume ratio
Dimethyl sulfoxide (DMSO) and tert-pentyl alcohol for 1:8～16 are reaction dissolvent, with mol ratio as 1:5～uridnine and the Palmic acid second of 13
Alkene ester is raw material, with 0.5～1.0g Lipozyme TLIM as catalyst, raw material and reaction dissolvent is placed in syringe,
Lipozyme TLIM is uniformly filled in reaction channel, makes raw material and reaction dissolvent continuous under the promotion of syringe pump
It is passed through in reaction channel device and carries out acylation reaction, make the concentration of uridnine in reaction system (being made up of raw material and reaction dissolvent) be
0.03～0.07mmol/mL, controlling acylation reaction temperature is 15～50 DEG C, and the acylation reaction time is 20～35min, is received by product
Reactant liquor collected online by storage, and reactant liquor obtains 5'-O-palmityl uridnine through conventional post processing.
In the microfluidic channel reactor that the present invention uses, described syringe number can be one or more, needs depending on specifically reacting
Depending on asking.Such as, when using two syringes, T-shaped or Y type interface can be used to make different reactants draw from two entrances
Enter, conflux and enter public reaction channel, contacted by the middle reactant molecule of microchannel and increase with collision probability, make two strands instead
Liquid stream is answered to mix in public reaction channel and react.
Described microfluidic channel reactor also includes that calorstat, described reaction channel are placed in calorstat, can be effective with this
Control reaction temperature.Described calorstat can require to select voluntarily according to reaction temperature, such as constant temperature water box etc..
The present invention does not limits for the material of reaction channel, it is recommended to use green, the material of environmental protection, such as silica gel tube；For reaction
The shape of passage is preferably shaped form, it is ensured that the most stable the passing through of reactant liquor.
The present invention, in implementation process, first dissolves uridnine with DMSO, is further continued for adding tert-pentyl alcohol to certain volume, is loaded on syringe
In standby；Then with tert-pentyl alcohol dissolving vinyl palmitate to certain volume, it is loaded in another syringe standby；Finally in injection
Make raw material and reaction dissolvent be passed through in reaction channel under pump (such as PD 1200 syringe pump) promotion to react.
In the present invention, described Lipozyme TLIM uses the commodity that letter (Novozymes) company of Novi produces, its
It is a kind of that prepared by microorganism, 1,3 position-specific, the food-grade lipase (EC3.1.1.3) preparation on particle silica gel.
It obtains from Thermomyceslanuginosus, with the microorganism of a kind of gene-modified aspergillus oryzae (Aspergillusoryzae)
Produce through submerged fermentation.
Further, in described reaction dissolvent, the volume ratio of dimethyl sulfoxide and tert-pentyl alcohol is preferably 1:12～1:16, preferably 1:14.
Further, described uridnine is preferably 1:9～11, most preferably 1:9 with the mol ratio of vinyl palmitate.
Further, in reaction system, the concentration of uridnine is preferably 0.04～0.06mmol/mL, most preferably 0.05mmol/mL.
Further, described acylation reaction temperature is preferably 20～40 DEG C, most preferably 30 DEG C.
Further, the described acylation reaction time is preferably 25～35min, most preferably 30min.
The product of the present invention can be collected online, and gained reactant liquor can obtain 5'-O-palm fibre by conventional post-processing approach
Palmitic acid ureide glycosides.Described conventional post-processing approach may is that the decompression of gained reactant liquor is distilled off solvent, with 200-300 mesh silica gel
Wet method dress post, elution reagent is ethyl acetate: methanol=40:1, sample wet method upper prop after the dissolving of a small amount of elution reagent, collects eluting
Liquid, TLC follows the tracks of eluting process simultaneously, is merged by the eluent containing single product obtained and is evaporated, can obtain white solid,
It is 5'-O-palmityl uridnine.
Compared with prior art, the invention have the benefit that the present invention utilizes in microfluidic channel reactor lipase-catalyzed
Online synthesis 5'-O-palmityl uridnine, this method not only significantly shortens the response time, and has high conversion ratio；The most first
The secondary Lipozyme TLIM utilizing economy is catalyzed nucleoside esterification, reduces reaction cost, has economical and efficient
Advantage.
(4) accompanying drawing explanation
Fig. 1 is the structural representation of the microfluidic channel reactor that the embodiment of the present invention uses.
(5) detailed description of the invention
With specific embodiment, protection scope of the present invention is described further below, but protection scope of the present invention is not limited to this:
Structural reference Fig. 1 of microfluidic channel reactor that the embodiment of the present invention uses, including a syringe pump (not shown), two
Individual syringe 1 and 2, reaction channel 3, constant temperature water box (5, only show its floor map) and product collector 4；Two
Individual syringe 1 and 2 is installed in syringe pump, is connected with reaction channel 3 entrance by a Y type interface, described reaction channel
3 are placed in constant temperature water box 5, control reaction temperature by constant temperature water box 5, the internal diameter 2.0mm of described reaction channel 3,
Pipe range 1m, described reaction channel 3 is exported and is connected with product collector 4 by an interface.
The synthesis of embodiment 1:5'-O-palmityl uridnine
Device is with reference to Fig. 1: be dissolved in 1.2mLDMSO and 8.8mL tert-pentyl alcohol by uridnine (1.0mmol), Palmic acid second
Alkene ester (9.0mmol, 2.3mL) is dissolved in 7.7mL tert-pentyl alcohol, is loaded in 10mL syringe standby the most respectively.0.87g
Lipozyme TLIM is uniformly filled in reaction channel, PD 1200 syringe pump promote under, two-way reactant liquor respectively with
10.4μL·min-1Flow velocity entered in reaction channel by " Y " joint and react, control temperature of reactor by constant temperature water box
At 30 DEG C, reactant liquor is continuous flowing reactive 30min in reaction channel, and reaction result passes through thin layer chromatography TLC tracing detection.
Collected reactant liquor online by product collector, decompression is distilled off solvent, fills post by 200-300 mesh silica gel wet method, washes
De-reagent is ethyl acetate: methanol=40:1, post height 35cm, column diameter 4.5cm, sample wet method after the dissolving of a small amount of elution reagent
Upper prop, flow velocity 2mL min collected by eluent-1, TLC follows the tracks of eluting process, the eluting containing single product that will obtain simultaneously
Liquid merging is evaporated, and obtains white solid, it is thus achieved that 5'-O-palmityl uridnine, and HPLC detects uridnine conversion ratio 99%, selectivity 100%.
Nuclear-magnetism characterization result is as follows:
1H-NMR(DMSO-d6, δ, ppm): 11.36 (s, H3), 7.61 (d, J=9Hz, H6), 5.75 (d, 1H, J=4.5Hz, H1'),
5.65 (d, 1H, J=9Hz, H5), 5.48 (d, 1H, J=5.5Hz, 3'-OH), 5.29 (d, 1H, J=5.5Hz, 2'-OH), 4.23 (m,
2H,H2'+H3'),4.07(m,1H,H4'),3.97(m,2H,H5'), 2.33 (t, 2H, J=7Hz, H2”),1.51(m,2H,H3”),
1.23(br,24H,H4”+H5”+H6”+H7”+H8”+H9”+H10”+H11”+H12”+H13”+H14”+H15”),0.85(t,
3H, J=7Hz, H16”).
13C NMR(DMSO-d6, ppm): 172.77 (C1”),163.04(C4),150.60(C2),140.76(C6),102.02(C5),88.76
(C1'),81.06(C4'),72.75(C3'),69.77(C2'),63.51(C5'),33.37(C2”),31.28(C14”),28.41-29.02(C4”+
C5”+C6”+C7”+C8”+C9”+C10”+C11”+C12'+C13”),24.41(C3”),22.08(C15”),13.94(C16”).
Embodiment 2-6
Keep organic total solvent volume consumption constant, change organic solvent DMSO and the body of tert-pentyl alcohol in microfluidic channel reactor
Long-pending ratio, controlling temperature is 50 DEG C, and other are with embodiment 1, and reaction result is as shown in table 1:
Table 1: the impact of organic solvent comparison reaction
The result of table 1 shows, when flow velocity is 10.4 μ L min-1, the response time is 30min, and reaction temperature is 50 DEG C,
Reactant uridnine and vinyl palmitate mol ratio are 1:9, and when uridnine concentration is 0.05mmol/mL, conversion ratio is with reaction
In device, organic solvent volume increases than increasing, and reaches optimal when DMSO reaches 1:14 with tert-butyl alcohol volume ratio, is further continued for
Increasing volume ratio will cause reactant to dissolve incomplete and reduce conversion ratio.So in the present invention in micro-fluidic micro passage reaction
Optimal organic solvent volume ratio is for 1:14.
Embodiment 7-11
Change uridnine and the substrate ratio of vinyl palmitate in micro-fluidic micro passage reaction, control other same embodiments of temperature 50 C
1, result is as shown in table 2:
Table 2: the impact that uridnine reacts with vinyl palmitate substrate comparison
The result of table 2 shows, when flow velocity is 10.4 μ L min-1, the response time is 30min, and reaction temperature is 50 DEG C,
In reactor, organic solvent DMSO and tert-butyl alcohol volume ratio are 1:14, when uridnine concentration is 0.05mmol/mL, along with
The increase of reactant vinyl palmitate, the conversion ratio of reaction also increases as, when substrate ratio is during for 1:9, the conversion ratio of reaction
Optimum, so in micro-fluidic micro passage reaction, optimal substrate mol ratio is 1:9 in the present invention.
Embodiment 12-15
Changing the temperature of microfluidic channel reactor, other are with embodiment 1, and reaction result is as shown in table 3:
Table 3: the temperature impact on reaction
The result of table 3 shows, when flow velocity is 10.4 μ L min-1, the response time is 30min, organic solvent DMSO in reactor
Being 1:14 with tert-butyl alcohol volume ratio, reactant uridnine and vinyl palmitate mol ratio are 1:9, and uridnine concentration is
During 0.05mmol/mL, when reaction temperature is in 30 DEG C, the conversion ratio of reaction is optimal, temperature or the highest or the lowest all by impact
The activity of enzyme.So in micro-fluidic micro passage reaction, optimum temperature is 30 DEG C in the present invention.
Embodiment 16-18
Changing the response time of microfluidic channel reactor, other are with embodiment 1, and reaction result is as shown in table 4:
Table 4: the response time impact on reaction
The result of table 4 shows, when in reactor, organic solvent DMSO and tert-butyl alcohol volume ratio are 1:14, reactant uridnine with
Vinyl palmitate mol ratio is 1:9, and reaction temperature is 30 DEG C, when uridnine concentration is 0.05mmol/mL, works as reaction
The when that time being 30min, reaction conversion ratio is up to 99%, converts the most completely.So micro-fluidic microchannel plate in the present invention
Answering optimum reacting time in device is 30min.
Embodiment 19-22
Changing the concentration of microfluidic channel reactant, other are with embodiment 1, and reaction result is as shown in table 5:
Table 5: the reactant concentration impact on reaction
The result of table 5 shows, when in reactor, organic solvent DMSO and tert-butyl alcohol volume ratio are 1:14, reactant uridnine
Being 1:9 with vinyl palmitate mol ratio, reaction temperature is 30 DEG C, and the response time is 30min, and uridnine concentration is
The when of 0.05mmol/mL, reaction conversion ratio is up to 99%, so optimum response in micro-fluidic micro passage reaction in the present invention
Substrate concentration is 0.1mmol/mL.
Comparative example 1-3
Change the catalyst in micro-fluidic micro passage reaction, change into respectively Lipozyme RM IM (comparative example 1),
Lipase Novozym 435 (comparative example 2), bacillus alkaline protease (comparative example 3), other are with embodiment 1, result
As shown in table 6.
Table 6: different enzymes on reaction conversion ratio and optionally affect
The result of table 6 shows, for the regioselectivity esterification of enzymatic uridnine in microfluidic channel reactor, different
Enzyme on reaction have fairly obvious impact.Utilize Lipozyme RMIM catalytic reaction, 5'-O-palmityl uridnine
Conversion ratio is 55%.And utilizing bacillus alkaline protease to be catalyzed this reaction, the conversion ratio of 5'-O-palmityl uridnine is only 16%.
In terms of the result of table 6, for the regioselectivity esterification of enzymatic uridnine in microfluidic channel reactor, maximally effective
Catalyst is Lipozyme TLIM, and the conversion ratio of uridnine is 99%, and selectivity is 100%.
Comparative example 4-5
Change different types of uridnine compound in micro-fluidic micro passage reaction, the uridnine 1mmol of embodiment 1 is changed into respectively
Guanosine 1mmol (comparative example 4), 3'-BrdU 1mmol (comparative example 5), other with embodiment 1, result is as shown in table 7.
Table 7: the different IPs glycosides compound impact on reaction
The result of table 7 shows, in microfluidic channel reactor enzymatic nucleoside compound regioselectivity esterification and
Speech, different nucleoside compounds has different reaction results.Under the same reaction conditions, conversion ratio is only for 3'-BrdU
It is 30%, reacts relatively difficult.The reaction result of guanosine is the most undesirable, and conversion ratio is only 37%.In terms of the result of table 7, right
In microfluidic channel reactor for the regioselectivity esterification of enzymatic nucleoside compound, uridnine can obtain and compare reason
The reaction result thought, the conversion ratio of reaction can reach 99%, and selectivity is 100%.
Claims (6)
1. a method for a kind of lipase-catalyzed online synthesis 5'-O-palmityl uridnine of lipase-catalyzed online synthesis, its feature
Being that described method uses microfluidic channel reactor, described microfluidic channel reactor includes syringe pump, syringe, reaction
Passage and product collector, described syringe is installed in syringe pump, is connected with reaction channel entrance by an interface, described
Product collector is connected with reaction channel outlet by an interface, and described reaction channel internal diameter is 0.8～2.4mm, reaction channel
A length of 0.5～1.0m；Described method includes: with volume ratio as 1:8～the dimethyl sulfoxide of 16 and tert-pentyl alcohol are as reaction dissolvent, with mole
It is raw material than uridnine and the vinyl palmitate for 1:5～13, with 0.5～1.0g Lipozyme TLIM as catalyst, will
Raw material and reaction dissolvent are placed in syringe, are uniformly filled in reaction channel by Lipozyme TLIM, at syringe pump
Promotion under make raw material and reaction dissolvent be passed through continuously in reaction channel device to carry out acylation reaction, make the concentration of uridnine in reaction system
Being 0.03～0.07mmol/mL, controlling acylation reaction temperature is 15～50 DEG C, and the acylation reaction time is 20～35min, passes through product
Catcher collects reactant liquor online, and reactant liquor obtains 5'-O-palmityl uridnine through conventional post processing.
The method of lipase-catalyzed online synthesis 5'-O-palmityl uridnine the most as claimed in claim 1, it is characterised in that: institute
The method stated comprises the following steps: to be first that solvent dissolves uridnine with a certain amount of DMSO, then adds tert-pentyl alcohol to certain volume, dress
In syringe standby；With tert-pentyl alcohol dissolving vinyl palmitate to certain volume, it is loaded in another syringe standby；Then exist
Make raw material and reaction dissolvent be passed through in reaction channel under syringe pump promotion to react.
The method of lipase-catalyzed online synthesis 5'-O-palmityl uridnine the most as claimed in claim 1, it is characterised in that: institute
State microfluidic channel reactor and include that calorstat, described reaction channel are placed in calorstat.
The method of lipase-catalyzed online synthesis 5'-O-palmityl uridnine the most as claimed in claim 2, it is characterised in that: institute
State microfluidic channel reactor and include that calorstat, described reaction channel are placed in calorstat.
5. the method for the lipase-catalyzed online synthesis 5'-O-palmityl uridnine as described in one of Claims 1 to 4, it is characterised in that:
In described reaction dissolvent, dimethyl sulfoxide is 1:12～16 with the volume ratio of tert-pentyl alcohol, described uridnine and the mol ratio of vinyl acetate on Palmic acid
For 1:9～11, in reaction system, the concentration of uridnine is 0.04～0.06mmol/mL, and described acylation reaction temperature is 20～40 DEG C, described
The acylation reaction time is 25～35min.
6. the method for the lipase-catalyzed online synthesis 5'-O-palmityl uridnine as described in one of Claims 1 to 4, its feature exists
In: in described reaction dissolvent, dimethyl sulfoxide is 1:14 with the volume ratio of tert-pentyl alcohol, described uridnine and the mol ratio of vinyl palmitate
For 1:9, in reaction system, the concentration of uridnine is that described in 0.05mmol/mL, acylation reaction temperature is 30 DEG C, during described acylation reaction
Between be 30min.
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| CN107955823A (en) * | 2017-12-21 | 2018-04-24 | 浙江工业大学 | A kind of method of lipase-catalyzed online synthesis 6- ((4- methyl-benzyls) sulfenyl) -6- oxo vinyl caproates |
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